Demyelinating diseases have long been known to be associated with behavioral disturbances. The expression levels of several myelin-related genes are consistently and substantially lower in brains obtained from schizophrenic patients than in control cases. Diffusion tensor imaging (DTI), an in vivo magnetic resonance imaging technique which assesses the coherence of white matter tracts, reveals a marked decrease in anisotropy in schizophrenic patients, indicating changes in the directionality and alignment of axons. Magnetic transfer imaging (MTI) further demonstrates reduction in myelin content in schizophrenia. An explanation for the decreased expression of myelin-related genes in schizophrenia and for the fact that these genes differentiate control from schizophrenic cases is that oligodendroglial cells are dysfunctional in schizophrenia. We propose a thorough quantitative analysis of oligodendroglial pathology in cortical and subcortical regions in brains obtained from schizophrenic patients, and a characterization of the possible repercussions of such disruption of specific axonal pathways on the morphology and function of neocortical neuron populations in genetically modified mouse models in which myelin-related genes have been knocked out. We will use rigorous stereologic analyses to assess possible changes in the numbers of oligodendrocytes in the cerebral cortex or the thalamus in schizophrenia. The 3-dimensional, spatial distribution of oligodendrocytes in these pathways may be consequently modified and may offer a quantitative neuropathological correlate of the changes in myelination. We will estimate this parameter using stereologic tessellation algorithms and relate these analyses to in vivo data obtained by DTI and MTI in other components of this Center. Finally, disruption of myelination resulting from knocking out specific myelin-related genes in mice will likely affect the organization of axonal pathways furnishing inputs to the neocortex. We will measure the degree of complexity of the dendritic arborization in reconstructed pyramidal neurons from such mice models. Changes in spine density, volume, and morphology, as well as ultrastructural changes in myelination will be quantified in these mice to assess how these parameters are modified by the myelination deficits. The human cases and the animal models studied within the context of this program offer an opportunity to analyze oligodendroglial changes that have a clinical impact and to determine the morphologic characteristics of the circuits whose alteration Ieads to the cortical and subcortical dysfunction that possibly underlies the pathogenesis of schizophrenia.